RESEARCH PROJECT 3 ? PROJECT SUMMARY There are considerable and persistent racial disparities in prostate cancer outcomes. Prostate cancer disproportionately affects African American men in terms of incidence, morbidity, and mortality, even after adjustment for stage. African American men have a 2- to 3- times increased risk of developing prostate cancer and have a greater mortality rate compared to white men. Racial disparities in prostate cancer outcomes mirror racial differences in vitamin D levels. African American men exhibit a high prevalence of vitamin D deficiency; several studies have shown that a majority of African American men has sub-optimal levels of circulating vitamin D. For this reason, vitamin D3 supplementation is likely to particularly benefit these men. Vitamin D promotes the differentiation of prostate cancer cells and maintains the differentiated phenotype of prostate epithelial cells, raising the possibility that long-term vitamin D deficiency may contribute to the progression of subclinical prostate cancer to clinical disease, especially among African American men. Therefore, eliminating racial disparities in circulating levels of vitamin D could have important implications for reducing disparities in prostate cancer outcomes. This MUSC-based research team has shown that supplementation eliminates racial disparities in serum levels of 25(OH)D between African American and white men, and that vitamin D3 supplementation at 4000 international units (IU) per day may benefit patients with low-risk prostate cancer on active surveillance. The investigators plan to conduct a study enrolling African American and white men who have been diagnosed with prostate cancer and have selected prostatectomy as a definitive treatment. These subjects will be randomized to vitamin D3 supplementation at 4000 IU per day (or placebo) for two months, before undergoing surgery. They plan to assess the transcription profiles in prostate tissue specimens collected from these subjects at time of surgery, using RNA sequencing (RNA-seq) technology. The main objectives of this application are to determine a) whether there are significant differences in transcription within prostate tissue specimens between African American and white men; b) whether vitamin D3 supplementation at 4000 IU per day for two months, compared to placebo, will significantly affect transcription in prostate tissue specimens from enrolled subjects; and c) whether genes involved in the hypothalamic-pituitary-adrenal (HPA) axis are differentially expressed in the prostate between African American and white men and how vitamin D3 supplementation affects the HPA axis. Comparison of transcription profiles and biological pathways between subjects enrolled in the treatment or the placebo arm of the study will also allow us to establish whether vitamin D3 supplementation is beneficial to the prostate and as a preventive and/or therapeutic option for early-stage prostate cancer, especially among African American men.